The hippocampus is critical for the formation and consolidation of spatial memories and, through its efferent projections, also contributes to other cognitive tasks. The goal of this project is to determine whether altered neuronal network activity in the hippocampus of a mouse model of autism propagates to, and alters distal cortical regions involved in social behaviors. A deficit in social interaction is one of the core symptoms of autism spectrum disorders, which includes Rett syndrome (RTT), a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional regulator MECP2. Altering the excitation and inhibition (E/I) balance in the medial prefrontal cortex (mPFC) of mice causes social behavior impairments reminiscent of autism spectrum disorders. The ventral hippocampus (vHIP) of Mecp2 knockout mice (KO) mice is hyperactive due to an E/I imbalance driven by impaired inhibition and enhanced excitation, which results in saturated synaptic plasticity at excitatory synapses. Intriguingly, CA1 pyramidal neurons of the vHIP project their axons to the mPFC, making direct monosynaptic connections with excitatory pyramidal neurons and inhibitory interneurons. We propose to characterize the influence of the vHIP on the activity of the mPFC through this long-range monosynaptic glutamatergic projection, testing whether altered vHIP network activity is causal to mPFC dysfunction and social interaction deficits. We hypothesize that hyperactive hippocampal afferents alter network activity in the mPFC of Mecp2 KO mice by affecting the E/I balance, which contributes to social interaction deficits. To test this hypothesis, we will identify the cellular targets of direct vHIP afferents in the mPFC of RTT mice and characterize their function and role in social behaviors using a combination of optogenetics, chemogenetics, ex vivo and in vivo electrophysiology and Ca2+ imaging, anterograde and retrograde tract tracing, and behavioral assessments. We propose the following Specific Aims: (1) characterize the cellular targets of the monosynaptic projection from the vHIP to the mPFC in Mecp2 KO mice; (2) characterize synaptic function and long-term synaptic plasticity of the monosynaptic projection from the vHIP to the mPFC in Mecp2 KO mice; (3) test if chemogenetic modulation of vHIP activity restores mPFC network activity and social behaviors in Mecp2 KO mice. In addition to defining novel pathophysiological mechanisms of RTT, these studies will provide fundamental information regarding the functional and structural properties of the long-range monosynaptic connection between the vHIP and mPFC in typically developing brains. Thus, the impact of this work will extend beyond RTT to other neuropsychiatric disorders in which propagation of network dysfunction from the hippocampus to the mPFC is thought to contribute to cognitive deficits.